RESEARCH AND RELATED Other Project Information PROJECT SUMMARY/ABSTRACT Venous thrombosis (VT) and pulmonary embolism (PE), collectively venous thromboembolism (VTE), affect over 1 million Americans annually. VT is initiated by intravascular activation of coagulation resulting in thrombin generation and fibrin deposition. Trapping of red blood cells (RBCs) within the developing fibrin network promotes thrombus growth, culminating in production of an occlusive fibrin- and RBC-rich thrombus. The long- term goals of our research program are to define cellular and molecular mechanisms that lead to VTE and develop new approaches for treatment and prevention. During the recent funding period we identified previously-unrecognized roles for fibrin(ogen), factor XIII (FXIII), and fibrin crosslinking in VT pathogenesis. Most prominently, we discovered that increased fibrin density and FXIIIa-mediated fibrin crosslinking enhance RBC retention in thrombi and promote the formation of larger thrombi, that genetic reduction of FXIII reduces thrombus size in wild-type mice, and that plasma FXIII, but not platelet FXIII, drives RBC retention in thrombi and thrombus growth. These findings support the scientific premise of this proposal that reducing plasma FXIII protein or activity and therefore, preventing trapping of RBCs in thrombi, will decrease VTE pathogenesis. The overall objective of this proposal is to determine mechanisms by which FXIII and fibrin crosslinking affect VT and PE risk. Our central hypothesis is that fibrin structure, crosslinking, and resistance to lysis are key determinants of thrombus formation and stability. We will use genetic and pharmacologic methods in human and mouse experimental systems to determine the impact of FXIII(a) reduction on VT associated with common hypercoagulable risk factors. We will employ a new murine model developed in our laboratory that recapitulates VT with subsequent PE to investigate mechanisms coupling FXIII to PE risk. We will also elucidate cellular and molecular determinants of unique reciprocal, inter-tissue regulation of plasma FXIII expression. Identifying these mechanisms is significant because it will reveal molecular and cellular events that promote VTE and characterize FXIII as a new potential therapeutic target for reducing VTE. Since VTE increases with age, cancer, pregnancy, oral contraceptive use, obesity, and following surgery, our findings will have broad implications for decreasing morbidity and mortality in numerous diseases.